Mevalonate phosphate kinase

Shama Bhat, C. Ramasarma, T. Inhibition of rat liver mevalonate pyrophosphate decarboxylase and mevalonate phosphate kinase by phenyl and phenolic compounds. Biochem. J., 181, 143-151 (1979)... 

Mevalonate kinase and mevalonate phosphate kinase activities both decrease in rats fed cholesterol [211]. 

Bhat, C.S. and Ramasarma, T., Effect of phenyl and phenolic acids on mevalonate-5-phosphate kinase and mevalonate-5-pyrophosphate decarboxylase of the rat brain, J. Neurochem., 32, 1531, 1979. 

In animals all isoprenoid compounds are apparently synthesized from mevalonate, which is converted by the consecutive action of two kinases21 23 into mevalonate 5-diphosphate (Fig. 22-1, step b). Mevalonate kinase is found predominantly in peroxisomes, which are also active in other aspects of steroid synthesis in humans.2124 A deficiency of this enzyme is associated with mevalonic aciduria, a serious hereditary disease in which both blood and urine contain very high concentrations of mevalonate.23 Mevalonate diphosphate kinase, which is also a decarboxylase, catalyzes phosphorylation of the 3-OH group of mevalonate (step c, Fig. 22-1) and decarboxylative elimination of phosphate (step d)25 to form isopentenyl diphosphate. 

MVAK mevalonate kinase PMK phosphomevalonate kinase DPMD diphosphomevaionate decarboxyiase PMD phosphomevaionate decarboxyiase iPK isopentenyi phosphate kinase... 

Step 4 of Figure 27.7 Phosphorylation and Decarboxylation Three addition reactions are needed to convert mevalonate to isopentenyl diphosphate. Th first two are straightforward phosphorylations that occur by nucleophilic sul stitution reactions on the terminal phosphorus of ATP. Mevalonate is first cor verted to mevalonate 5-phosphate (phosphomevalonate) by reaction wit ATP in a process catalyzed by mevalonate kinase. Mevalonate 5-phosphat then reacts with a second ATP to give mevalonate 5-diphosphate (diphosphc mevalonate). The third reaction results in phosphorylation of the tertiar hydroxyi group, followed by decarboxylation and loss of phosphate ion. 

Further work on the enzymes of the early stages of terpenoid biosynthesis continues. Mevalonic kinase (EC 2.7.1.36) from hog liver has been shownto have a molecular weight of about 98 000 and to react first with mevalonic acid, then with magnesium and ATP, to release first the 5-phosphate and then ADP. The corresponding kinase from rat.ovary seems to differ from the liver enzyme. Mevalonic kinase was found to be present in many tissues of an insect larva. 

Phosphomevalonate kinase (PMK, EC 2.7.4.2) is the enzyme involved in the second step of the terpenoid biosynthesis and catalyzes the reversible conversion of mevalonate 5-phosphate and ATP to mevalonate 5-diphosphate and ADP, a key step in that synthesis. Fig. (6), [289-290]. Kinetic characterisation of PMK has been carried out using enzymes from mainly animal sources including human, S. cerevisiae and some plants. In addition, PMK has only been partially purified and characterized. It seems that this enzyme is quite a unique enzyme, but its characteristics reveal some remarkable differences among diverse sources. Thus, pig liver and human liver PMKs show molecular weights between 21 and 22 kDa [291-292], whereas the enzyme isolate from S. cerevisiae has a molecular weight of 47 kDa [293]. 

Mevalonate ((118), Figure 6.27) is a key intermediate, and mevalonate kinase is a key early enzyme, in isoprenoid and sterol synthesis. Inhibitors of this enzyme have potential applications for treatment of cardiovascular disease and cancer. Mevalonate kinase activity is controlled post-transcriptionally via competitive inhibition at the ATP site by prenyl phosphates, such as geranyl diphosphate (119). A bifunctional inhibitor with micromolar IC50 values against mevalonate kinase and mevalonate 5-diphosphate decarboxylase (a... 

The hydroxyl groups in mevalonate are then esterified in a stepwise fashion to their phosphates by phosphorylating enzymes, called kinases. The overall result is the intermediate 1-4 in which the terminal hydroxyl is a diphosphate and the tertiary hydroxyl is present as a monophosphate, the latter comprising a very good leaving group. The next step consists of decarboxylation with concomitant departure of the tertiary phosphate group. This transformation finally affords the latent isoprene unit 1-5. The product from this sequence, IPP (1-5), is reversibly converted to its isomer with the internal double bond (1-6) by yet another enzyme. 

Figure 2.11. Lipid synthesis. GDP = glycerol-3-phosphate dehydrogenase. PP = phosphat-idate phosphatase. CPT=choline phosphotransferase. BPT= ethanolamine phosphotransferase. AC = acetyl CoA carboxylase. HAD 3-hydroxyacyl-CoA dehydrogenase. CCPT = cemmide choline phosphotransferase. HMGR = hydroxymethyl utaryl-CoA reductase. MK = mevalonate kinase. IPPI = isopentenyl pyrophosphate isomerase...

Then (Scheme 11.41) mevalonate [(l )-3,5-dihydroxy-3-methylpentanoic acid] is phosphorylated by the enzyme mevalonate kinase (EC 2.7.1.36) at the primary hydroxyl. The phosphate that is added is obtained (an addition-elimination reaction or a displacement reaction) from the terminal phosphate group of ATP forming ADP in turn. Another phosphorylation, again using ATP yields mevalonate diphosphate, this time by the enzyme phosphomevalonate kinase (EC 2.7.4.2) and then, after one more phosphorylation, this time on the tertiary hydroxyl, decarboxylation and dehydration co-occur, catalyzed by the enzyme mevalonate diphosphate decarboxylase (EC 4.1.1.43). The products are inorganic phosphate, carbon dioxide, and isopentenyl diphosphate (diphosphoric acid mono[3-methylbut-3-enyl] ester). Isopentenyl diphosphate isomerase (EC S.3.3.2) catalyzes the isomerization, via loss of the C2 pro-R hydrogen, between isopentenyl diphosphate and dimethylallyl diphosphate. 

The steps required to convert mevalonic acid to the active-isoprenoid intermediate have been worked out with some assurance. The initial step involves the phosphorylation of mevalonic acid to mevalonic acid-5-phosphate by an enzyme called mevalonic kinase. This enzyme was found in yeast by Tchen (1958). The properties of the mevalonic kinase of liver have been described in detail by Levy and PopjAK (1960). The kinase is inhibited by p-chloromercuribenzoate but not by iodoacetamide. The enzyme requires Mg++, Mn++, or Ca++ and ATP or inosine triphosphate. The kinase is specific for the (+) form of mevalonic acid. Mevalonic acid-5-phosphate is phosphorylated further to give mevalonic acid-5-pyrophos-phate (de Waard and Popjak, 1959 Henning et al. 1959). The purified enzyme (Bloch et al., 1959) requires a divalent metal ion for activity (Mg++ is preferable) and has no pronounced pH optimum. Mevalonic acid pyrophosphate then undergoes simultaneous dehydration and decarboxylation to yield isopentenylpyro-phosphate (Lynen et al., 1958 Chaykin et al., 1958). The enzyme concerned with the dehydration and decarboxylation has been purified (Bloch et al., 1959) and shown to have a pH optimum between 5.5 and 7.4 and to require a divalent metal ion (Mg++, Mn++, Fe++ or Co++). The series of reactions in which mevalonate is converted to isopentenylpyrophosphate is outlined in Figure 6. Brodie et al. (1963) have established a new pathway for the biosynthesis of mevalonic acid from malonyl CoA. The importance of this particular pathway in the synthesis of sterols is still unknown. 

Mevalonate kinase [E.C.2.7.1.36 (5) -> (6)] preparations from several plants are inhibited by geranyl, geranylgeranyl, farnesyl, and phytyl pyrophosphates, the most potent inhibitors being the latter two compounds.This enzyme may, therefore, be a control point of isoprenoid biosynthesis in plants. A cell-free system for conversion of mevalonic acid (5) into mevalonic acid S-pyro-phosphate (7) has been prepared from the sapogenin-producing plant Agave americana. ... 

As soon as mevalonate acid has formed, a series of enzymes are involved in order to transform MVA to IPP. Mevalonate kinase [EC 2.7.1.36] phosphorylates the primary alcohol to mevalonate 5-phosphate, whereas phosphomevalonate kinase [EC 2.7.4.2] produces 5-pyrophosphomevalonate... 

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